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Twist1 in Infiltrating Macrophages Attenuates Kidney Fibrosis via Matrix Metallopeptidase 13-Mediated Matrix Degradation.

Publication ,  Journal Article
Ren, J; Zhang, J; Rudemiller, NP; Griffiths, R; Wen, Y; Lu, X; Privratsky, JR; Gunn, MD; Crowley, SD
Published in: J Am Soc Nephrol
September 2019

BACKGROUND: Following an acute insult, macrophages regulate renal fibrogenesis through the release of various factors that either encourage the synthesis of extracellular matrix synthesis or the degradation of matrix via endocytosis, proteolysis, or both. However, the roles of infiltrating versus resident myeloid cells in these opposing processes require elucidation. The transcription factor Twist1 controls diverse essential cellular functions through induction of several downstream targets, including matrix metalloproteinases (MMPs). In macrophages, Twist1 can influence patterns of cytokine generation, but the role of macrophage Twist1 in renal fibrogenesis remains undefined. METHODS: To study Twist1 functions in different macrophage subsets during kidney scar formation, we used two conditional mutant mouse models in which Twist1 was selectively ablated either in infiltrating, inflammatory macrophages or in resident tissue macrophages. We assessed fibrosis-related parameters, matrix metallopeptidase 13 (MMP13, or collagen 3, which catalyzes collagen degradation), inflammatory cytokines, and other factors in these Twist1-deficient mice compared with wild-type controls after subjecting the animals to unilateral ureteral obstruction. We also treated wild-type and Twist1-deficient mice with an MMP13 inhibitor after unilateral ureteral obstruction. RESULTS: Twist1 in infiltrating inflammatory macrophages but not in resident macrophages limited kidney fibrosis after ureteral obstruction by driving extracellular matrix degradation. Moreover, deletion of Twist1 in infiltrating macrophages attenuated the expression of MMP13 in CD11b+Ly6Clo myeloid cells. Inhibition of MMP13 abrogated the protection from renal fibrosis afforded by macrophage Twist1. CONCLUSIONS: Twist1 in infiltrating myeloid cells mitigates interstitial matrix accumulation in the injured kidney by promoting MMP13 production, which drives extracellular matrix degradation. These data highlight the complex cell-specific actions of Twist1 in the pathogenesis of kidney fibrosis.

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Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

September 2019

Volume

30

Issue

9

Start / End Page

1674 / 1685

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Ureteral Obstruction
  • Twist-Related Protein 1
  • Myeloid Cells
  • Morpholines
  • Mice
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinase 13
  • Male
  • Macrophages, Peritoneal
 

Citation

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Ren, J., Zhang, J., Rudemiller, N. P., Griffiths, R., Wen, Y., Lu, X., … Crowley, S. D. (2019). Twist1 in Infiltrating Macrophages Attenuates Kidney Fibrosis via Matrix Metallopeptidase 13-Mediated Matrix Degradation. J Am Soc Nephrol, 30(9), 1674–1685. https://doi.org/10.1681/ASN.2018121253
Ren, Jiafa, Jiandong Zhang, Nathan P. Rudemiller, Robert Griffiths, Yi Wen, Xiaohan Lu, Jamie R. Privratsky, Michael D. Gunn, and Steven D. Crowley. “Twist1 in Infiltrating Macrophages Attenuates Kidney Fibrosis via Matrix Metallopeptidase 13-Mediated Matrix Degradation.J Am Soc Nephrol 30, no. 9 (September 2019): 1674–85. https://doi.org/10.1681/ASN.2018121253.
Ren J, Zhang J, Rudemiller NP, Griffiths R, Wen Y, Lu X, et al. Twist1 in Infiltrating Macrophages Attenuates Kidney Fibrosis via Matrix Metallopeptidase 13-Mediated Matrix Degradation. J Am Soc Nephrol. 2019 Sep;30(9):1674–85.
Ren, Jiafa, et al. “Twist1 in Infiltrating Macrophages Attenuates Kidney Fibrosis via Matrix Metallopeptidase 13-Mediated Matrix Degradation.J Am Soc Nephrol, vol. 30, no. 9, Sept. 2019, pp. 1674–85. Pubmed, doi:10.1681/ASN.2018121253.
Ren J, Zhang J, Rudemiller NP, Griffiths R, Wen Y, Lu X, Privratsky JR, Gunn MD, Crowley SD. Twist1 in Infiltrating Macrophages Attenuates Kidney Fibrosis via Matrix Metallopeptidase 13-Mediated Matrix Degradation. J Am Soc Nephrol. 2019 Sep;30(9):1674–1685.

Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

September 2019

Volume

30

Issue

9

Start / End Page

1674 / 1685

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Ureteral Obstruction
  • Twist-Related Protein 1
  • Myeloid Cells
  • Morpholines
  • Mice
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinase 13
  • Male
  • Macrophages, Peritoneal